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Total Synthesis of Hyperforin.

Sparling, Brian Andrew.

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Total Synthesis of Hyperforin.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Total Synthesis of Hyperforin./
Author:	Sparling, Brian Andrew.
Description:	555 p.
Notes:	Source: Dissertation Abstracts International, Volume: 75-02(E), Section: B.
Contained By:	Dissertation Abstracts International75-02B(E).
Subject:	Chemistry, Organic. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3600252
ISBN:	9781303503160

Total Synthesis of Hyperforin.
Sparling, Brian Andrew.

Total Synthesis of Hyperforin. - 555 p.

Source: Dissertation Abstracts International, Volume: 75-02(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2013.

Hyperforin is the component of the medicinal herb St. John's Wort ( Hypericum perforatum) responsible for its antidepressant activity. It works by blocking the reuptake of a variety of neurotransmitters through a unique mechanism of action and may be a critical lead for the treatment of depression and possibly other human diseases. However, the therapeutic potential of hyperforin is severely handicapped by its poor water solubility, facile oxidative degradation, and potent activation of pregnane X receptor, leading to increased expression of many genes involved in xenobiotic metabolism. Access to a wide variety of hyperforin analogs is critical for mitigating these shortcomings while maintaining therapeutic activity. While limited semisynthetic manipulation of isolated hyperforin is feasible, total synthesis is the only possible means of obtaining diverse hyperforin analogs.

ISBN: 9781303503160Subjects--Topical Terms:

516206
Chemistry, Organic.

Total Synthesis of Hyperforin.
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020 $a 9781303503160
035 $a (MiAaPQ)AAI3600252
035 $a AAI3600252
040 $a MiAaPQ $c MiAaPQ
100 1 $a Sparling, Brian Andrew. $3 2101729
245 1 0 $a Total Synthesis of Hyperforin.
300 $a 555 p.
500 $a Source: Dissertation Abstracts International, Volume: 75-02(E), Section: B.
500 $a Adviser: Matthew D. Shair.
502 $a Thesis (Ph.D.)--Harvard University, 2013.
520 $a Hyperforin is the component of the medicinal herb St. John's Wort ( Hypericum perforatum) responsible for its antidepressant activity. It works by blocking the reuptake of a variety of neurotransmitters through a unique mechanism of action and may be a critical lead for the treatment of depression and possibly other human diseases. However, the therapeutic potential of hyperforin is severely handicapped by its poor water solubility, facile oxidative degradation, and potent activation of pregnane X receptor, leading to increased expression of many genes involved in xenobiotic metabolism. Access to a wide variety of hyperforin analogs is critical for mitigating these shortcomings while maintaining therapeutic activity. While limited semisynthetic manipulation of isolated hyperforin is feasible, total synthesis is the only possible means of obtaining diverse hyperforin analogs.
520 $a The goal of the work presented in this thesis was to devise a new enantioselective, versatile approach to hyperforin that would not only incorporate elements of modularity but also exploit latent symmetry within the natural product that would enable facile analog synthesis. Early strategies that we explored included the carbocyclic cyclization of a polyketide and the electrocyclic cascade reaction involving an acylketene. These strategies were inherently flawed, and we subsequently pursued an alternative approach involving a diastereoselective epoxide-opening cascade cyclization.
520 $a This approach led to the enantioselective total synthesis of hyperforin. The synthesis is 18 steps in its longest linear sequence and can be deconstructed as the stepwise fusion of six easily obtainable chemicals. The key step in this sequence involved a group-selective, Lewis acid-mediated epoxide-opening cyclization, in which the strategically placed epoxide functionality relayed stereochemical information to the C1, C5, and C8 carbon centers of hyperforin, allowing 2 quaternary stereocenters and the bicyclic core of hyperforin to be established in a single transformation. Using this 18-step sequence, we were able to synthesize over 40 mg of the natural product in a single batch.
520 $a Further, a small library of analogs has been synthesized using the framework of the hyperforin synthesis. These efforts have resulted in the first total synthesis of the natural product secohyperforin and the first enantioselective synthesis of (--)-nemorosone.
590 $a School code: 0084.
650 4 $a Chemistry, Organic. $3 516206
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0490
690 $a 0572
710 2 $a Harvard University. $b Chemistry and Chemical Biology. $3 2094763
773 0 $t Dissertation Abstracts International $g 75-02B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3600252